Mechanistic Lung Cancer

Despite well-documented health risks, a substantial
proportion of men and women in the developed world

continue to habitually smoke cigarettes
1
. Making mat-
ters worse, smoking prevalence rates are on the rise in
developing nations, all but ensuring an increased inci-
dence of cigarette smoking-related diseases in the years
to come. Given the paucity of disease-modifying thera-
pies for most of these disorders, substantial increases
in mortality are expected
2
. Of the numerous smoking-
related maladies coronary artery disease, periph-
eral vascular disease, urinary bladder cancer, stroke
and so on the most common is chronic obstructive
pulmonary disease (COPD), and the most deadly is
lung cancer. Thus, it has been a concerning revelation
that these two diseases are linked, with the presence
of COPD increasing the incidence of lung cancer and
lung cancerdeath
3
.
For decades, the occurrence of lung cancer in
patients with COPD was thought to reflect the common
aetiological agent, cigarettes. Observation of high lung
cancer incidence rates in specialty COPD clinics chal-
lenged this idea, and prompted controlled epidemio-
logical studies to address this question. First reported by
Skillrud and colleagues
4
in 1986, the presence of COPD,
as determined by a reduction in airflow, was associated
with an increase in lung cancer incidence. Subsequently,
this finding has been reproduced in numerous studies
with large sample sizes that have carefully controlled
for cigarette smoke dosage
59
(TABLE1). However, little
progress has been made towards identifying common
mechanistic links for these heterogeneous diseases,
which can both be characterized by multiple disease
sub-phenotypes.
COPD is loosely defined as the presence of airflow
obstruction (BOX1) in the setting of chronic exposure to
noxious particulate matter (cigarette smoke)
10
, and it is
comprised of two major components the obstruction
of the breathing tubes (airways disease) and the oblitera-
tion of the tiny air sacs in the peripheral regions of the
lung (emphysema)
11
. There is undoubtedly a substantial
component of genetic susceptibility to the development
of COPD, as only about 1525% of smokers will develop
one or both of the components of COPD. Currently,
an estimated 20 million Americans are afflicted with
COPD, which is the fourth leading cause of death in the
United States
12
.
Lung cancer is considerably less common than
COPD; however, it accounts for ~160,000 deaths annu-
ally in the United States, with only 15% of patients still
alive 5years after diagnosis
13
. Approximately 20% of
lung cancer cases are small-cell lung cancer (SCLC) by
histology, with the other 80%, which includes adeno-
carcinoma (ADCA), squamous cell carcinoma (SCCA),
large-cell carcinoma and bronchoalveolar cell carci-
noma, being lumped together as non-small-cell lung
cancer (NSCLC)
14
. It seems that each of these subtypes
of lung cancer is linked to COPD, although data are
somewhat limited with respect to uncommon histo-
logical subtypes. As with COPD, only a minority of
cigarette smokers will develop lung cancer, highlight-
ing the importance of genetic susceptibility to disease.
Furthermore, about 10% of lung cancers arise in people
who have never smoked (never smokers)
15
.
The link between these two diseases has garnered
substantial attention over the past few years owing to a
few insightful clinical studies and the looming burden on
Clinical Research Division,
Fred Hutchinson Cancer
Research Center and Division
of Pulmonary and Critical
Care, University of
Washington, Seattle,
Washington 98109, USA.
e-mail: houghton@fhcrc.org
doi:10.1038/nrc3477
Published online 7 March 2013
Mechanistic links between
COPD and lung cancer
A.McGarry Houghton
Abstract | Numerous epidemiological studies have consistently linked the presence of
chronic obstructive pulmonary disease (COPD) to the development of lung cancer,
independently of cigarette smoking dosage. The mechanistic explanation for this remains
poorly understood. Progress towards uncovering this link has been hampered by the
heterogeneous nature of the two disorders: each is characterized by multiple
sub-phenotypes of disease. In this Review, I discuss the nature of the link between the two
diseases and consider specific mechanisms that operate in both COPD and lung cancer,
some of which might represent either chemopreventive or chemotherapeutic targets.
REVIEWS
NATURE REVIEWS | CANCER ADVANCE ONLINE PUBLICATION | 1
Nature Reviews Cancer | AOP, published online 7 March 2013; doi:10.1038/nrc3477
2013 Macmillan Publishers Limited. All rights reserved
Proximal lung cancers
Proximal refers to cancers
arising in the large airways
(bronchi) that are easily
accessible by bronchoscopy.
These lesions are most
commonly squamous cell
carcinoma or small-cell lung
cancer by histology.
Distal lung cancers
Distal cancers arising in the
peripheral zones of the lung
are more difficult to sample
using bronchoscopy. These
lesions are most commonly
adenocarcinoma by histology.
healthcare systems worldwide
16
. Despite the increased
attention, the nature of the link between COPD and
lung cancer remains obscure. This is due, in large part,
to the seemingly polar opposite nature of the two dis-
eases. Emphysema is characterized by the destruction
of matrix structures, epithelial cell death and a vanish-
ing blood supply (alveolar capillary dropout). By stark
contrast, cancers display the ability to avoid apopto-
sis, proliferate uncontrollably and create new vascular
networks. However, as discussed below, there are key
shared mechanisms that may represent links between
these two diseases, and potentially chemopreventive or
chemotherapeutic targets.
Emphysema and airflow obstruction confer risk
Several studies subsequent to Skillruds seminal report
were able to confirm the original findings that COPD
increased cancer risk, but were unable to pinpoint which
aspects of COPD were involved. Fortunately, the increas-
ing use of computed tomography (CT) imaging of the
chest provided clinicians with a tool that could non-
invasively identify the presence of one key aspect of COPD
emphysema. Subsequently, researchers began to use this
methodology to sub-phenotype COPD subjects into those
with emphysema or airflow obstruction, or those with both.
Wilson and colleagues
17
used a patient cohort that was
defined in this way to demonstrate that the presence of
emphysema, even when controlled for airflow obstruc-
tion, conferred an increased risk of lung cancer
17
. Notably,
most of these studies also demonstrate a risk for declining
forced expiratory volume in 1second (FEV
1
), although
it remains unclear whether this is a surrogate marker
for emphysema, or, more likely, whether components of
COPD other than emphysema confer a proportion
of the risk. These findings have been reproduced in four
independent studies
1821
, and have not been refuted, with
the caveat that the presence of radiographic emphysema
was determined by semi-quantitative scoring by radiolo-
gists, and not by automated software programs that fail to
detect the presence of mild emphysema
22,23
. One of these
studies also demonstrated an increase in lung cancer
mortality, in addition to increased incidence
21
.
Unlike COPD, emphysema has a strict anatomical
definition: the permanent enlargement of the periph-
eral airspaces of the lung distal to the terminal
bronchioles. The pathology of emphysema can be char-
acterized by the presence of proteinases in excess of
their inhibitors, increased apoptosis of lung epithelial
and endothelial cells, excessive oxidative burden, and
an inflammatory cell infiltrate composed of CD4
+

and CD8
+
lymphocytes, as well as macrophages and
neutrophils
24
. The airways disease component of
COPD consists of a similar inflammatory cell infiltrate,
mucous hypersecretion, sub-epithelial cell fibrosis and
airway wall thickening
25
.
It remains unclear whether airways disease and air-
space disease confer a regional or a global risk of lung
cancer. Typically, airways disease and smoking exposure
would be associated with proximal lung cancers, such as
SCCA and SCLC. Similarly, emphysema, being a periph-
erally located disease, would assumedly nurture ADCA
development (distal lung cancers). Surprisingly, the lim-
ited data available on the subject suggest that emphy-
sema confers a greater risk for SCLC and SCCA, than
it does for ADCA
20
. Further studies with more carefully
phenotyped subjects will be required to definitively
answer this question.
Given the fact that COPD predisposes one to lung
cancer, emerging studies are now examining how the key
pathological features of the airways disease and airspace
disease in COPD may lead to lung cancer development
(FIG.1). The leading candidates are consideredbelow.
Mechanisms linking COPD and lung cancer
Genetic predisposition. COPD and lung cancer are prime
examples of the gene-by-environment theory of disease
pathogenesis. The responsible environmental exposure,
tobacco cigarette smoke, has been well documented for
both. However, only a small proportion of smokers will
develop either disease (or both), strongly implying a role
for genetic susceptibility to disease (TABLE2). There are
only two clearly established genetic causes of COPD, and
both of them cause an emphysema-predominant pheno-
type. One is cutis laxa, an inherited defect that results in
decreased elastic fibre content in the lungs and skin
26
, and
is sufficiently rare not to be discussed here. The other is
At a glance
Numerous epidemiological studies have consistently demonstrated an increased
incidence of lung cancer in patients who have chronic obstructive pulmonary
disease (COPD).
The emphysema component of COPD, which is characterized by excessive
inflammation and matrix destruction, is sufficient to confer an increased risk for lung
cancer. Taken together, the epidemiological literature suggests that entities involved
in the airways and airspace components of COPD are both operative in increasing
lung cancerrisk.
Both COPD and lung cancer involve a substantial role for genetic susceptibility to
disease, as only a minority of chronic cigarette smokers will develop one, or both, of
the diseases. Several single nucleotide polymorphisms (SNPs) in candidate gene
families (for example, detoxifying enzymes, proteinases, anti-proteinases and
cytokines) have been implicated in disease pathogenesis for both COPD and lung
cancer, and may confer a proportion of therisk.
The oxidant and noxious stress encountered in the lungs of cigarette smokers is
overwhelming. These species cause sufficient damage to some epithelial cells such
that they undergo apoptosis, resulting in emphysema. They additionally represent
genotoxic stress capable of DNA adduct formation, thereby promoting the earliest
stages of carcinogenesis.
Inflammatory cell infiltrates are common to both COPD and lung cancer. Their
quantity and quality must be taken in context. Inflammation encountered in
emphysema is typically cytotoxic and destructive to matrix structures. Such cells
would not be expect to promote the growth of an existing tumour, but would provide
the necessary genotoxic stress for tumour initiation. Once formed, small tumours
polarize immune cells to alternatively activated phenotypes, which promote tumour
growth and angiogenesis.
Matrix-degrading enzymes, especially those capable of degrading elastin (elastases)
are essential for the development of emphysema. Many of these enzymes have been
shown to promote lung tumour growth by a variety of mechanisms, including
enhanced cellular proliferation and increased angiogenesis, which permits
endovascular invasion. Therefore, these enzymes are likely to represent a proportion
of the link between emphysema and lungcancer.
As operative mechanisms linking COPD to lung cancer are discovered, the
opportunity for chemoprevention will arise. Ideally, new therapies will be developed
that have the ability to retard COPD progression while reducing lung cancerrisk.
REVI EWS
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A1AT
There are more than 75 known
mutations in SERPINA1. The
normal allele has been
designated M. The most
commonly encountered
abnormal alleles are Z and S.
A1AT deficiency is most
commonly seen in ZZ or SZ
subjects. Common carrier
states include MZ and MS.
a hereditary deficiency of 1 antitrypsin (A1AT; encoded
by SERPINA1). A1AT is the physiological inhibitor of
neutrophil elastase (NE; also known as HLE (encoded by
ELANE)), which is a potent neutrophil-derived proteinase
that is capable of degrading elastin, the rubber band
protein that provides the lung its ability to recoil follow-
ing inhalation
27
. Unfortunately, functional elastic fibres
cannot be generated after adolescence, and so emphysema
is thought to be an irreversible process
28
. Of the original
five subjects identified as A1AT-deficient, three also had
emphysema
29
. This observation formed the cornerstone
of the proteinaseantiproteinase hypothesis of emphy-
sema, which holds that when the proteinase burden in
the lungs exceeds that of the antiproteinase shield (A1AT),
elastin degradation and emphysema result
30
. Subsequent
studies using the intratracheal administration of elasto-
lytic enzymes into the lungs of rodents validated this
hypothesis by reproducing key features of emphysema
pathology
31
.
It remains unclear whether A1AT deficiency pro-
motes lung tumorigenesis. Patients homozygous for
the condition typically develop severe emphysema with
reduced (or no) cigarette smoke exposure, and have
shortened lifespans
32
. Therefore, these subjects benefit
from a limited carcinogen exposure that places them at
a low risk for cancer, and that possibly masks genetic
susceptibility. However, there is evidence that carriers
for A1AT deficiency are subject to a 70% increased risk
for lung cancer
33
. Additionally, the imbalance of exces-
sive NE activity coupled with reduced A1AT inhibitory
capacity has been shown to correlate with lung cancer
risk
34
. Mechanistically, A1AT deficiency could contrib-
ute to lung tumorigenesis through increased NE activ-
ity or due to the loss of the intracellular pro-apoptotic
properties ofA1AT
35
.
Genetic-mapping studies have identified several sin-
gle nucleotide polymorphisms (SNPs) that are associated
with both COPD and lung cancer. Many of these reside in
Table 1 | Studies linking COPD and lung cancer*
Study Number of
participants
Outcome FEV
1
(% predicted)
Emphysema
Skilrud etal.
4
226 Incidence Cancers in 8.8% of cases (FEV
1

<70%) versus 2.0% of controls
(FEV
1
>85%); P = 0.024
NA
Tockman etal.
5
4,395 Mortality Cohort 1: RR 4.85 for FEV
1
<60%
versus >60%; P = 0.002
Cohort 2: RR 2.72 for FEV
1

6085% versus >85%; P = 0.043
NA
Speizer etal.
7
8,427 Mortality Quartile-based FEV
1
analysis
confers cancer risk (RR 2.08.27)
NA
Lange etal.
6
13,946 Mortality RR 2.1 (95% CI 1.33.4) for FEV
1

4079% versus >80%
RR 3.9 (95% CI 2.27.2) for FEV
1

<40% versus >80%
NA
de Torres etal.
19
1,166 Incidence RR 2.89 (95% CI 1.147.27) for
FEV
1
/FVC ratio <70% versus
>70%
Semi-quantitative
radiographic emphysema, RR
3.13 (95% CI 1.327.44)
Wilson etal.
17
3,638 Incidence OR 2.09 (95% CI 1.333.27) for any
GOLD stage (FEV
1
/FVC <70%)
Semi-quantitative radiographic
emphysema, OR 3.56 (95% CI
2.215.73). After controlling
for airflow obstruction, OR
3.14 (95% CI 1.915.15) for
radiographic emphysema
Li etal.
20
1,015 Incidence NA Semi-quantitative radiographic
emphysema. Any = OR 2.79
(95% CI 2.053.81), >5% = 3.80
(95% CI 2.785.19), >10% = OR
3.33 (95% CI 2.304.82)
Zulueta etal.
21
9,047 Mortality NA Semi-quantitative
radiographic emphysema, HR
1.7 (95% CI 1.12.5); P = 0.013
Maldanado etal.
23
1,520 Incidence Cancer risk conferred by
decreasing FEV
1
, OR 1.15 (95% CI
1.001.32; P = 0.046); and FEV
1
/
FVC <70%, OR 1.29 (95% CI
1.021.62; P = 0.0310)
Automated volumetric
determination of radiographic
emphysema was not
associated with lung cancer
risk, OR 1.042 (95% CI,
0.8161.329; P = 0.743)
CI, confidence interval; FEV
1
, forced expiratory volume in 1second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic
Obstructive Lung Disease; HR, hazard ratio; NA, not applicable; OR, odds ratio; RR, relative risk. *All studies controlled for age and
cigarette consumption.
The FEV
1
is reported as the percentage that would be predicted for that individual based on parameters
that are known to influence the FEV
1
, such as gender, age, height and race.
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Nature Reviews | Cancer
Normal alveoli
Alveoli with emphysema
Normal bronchi
Bronchitis
candidate gene families, such as proteinases, detoxifying
enzymes and inflammatory cytokines (discussed below).
Other genes implicated in COPD pathogenesis in recent
linkage and genome-wide association studies (GWASs)
include SERPINE2, Hedgehog interacting protein (HHIP)
and family with sequence similarity 13, member A
(FAM13A)
3638
. The majority of GWASs carried out for
COPD or lung cancer have identified the same locus on
chromosome 15q25 that maps to CHRNA3 and CHRNA5,
which encode nicotinic acetylcholine receptors
3841
.
Although there is some evidence that nicotine could be
involved in lung cancer and COPD pathogenesis, it is dif-
ficult to ignore the fact that CHRNA3 and CHRNA5 are
also associated with cigarette smoke consumption and
nicotine dependence. As all of the diseases that have been
linked to CHRNA3 and CHRNA5 COPD, lung cancer,
peripheral vascular disease and nicotine dependence
are disorders that can arise as a result of cigarette smok-
ing, it is quite possible that they are simply functioning as
surrogates for tobacco smoke exposure.
Epigenetic changes may link COPD and lung can-
cer through common methylation markings and sub-
sequent changes in gene expression that are induced
by cigarette smoking. DNA hypermethylation has
been implicated in the altered expression of numer-
ous oncogenes and tumour suppressors in lung can-
cer, most notably for RAS association domain family
member 1 (RASSF1A), O-6-methylguanine-DNA
methyltransferase (MGMT), cyclin-dependent kinase
inhibitor 2A (CDKN2A), retinoblastoma 1 (RB1),
glutathione S-transferase (GSTP1) and transforming
growth factor- receptor II (TGFBRII)
4248
. Of these,
CDKN2A, which encodes the tumour suppressors p16
(also known as INK4A) and ARF, represents a common
methylation mark between COPD and lung cancer
42
.
The first genome-wide epigenetic study in COPD sub-
jects was recently completed and identified 349 CpG
sites that were significantly associated with COPD
49
.
Many of these sites have previously been reported to
confer lung cancerrisk.
Box 1 | COPD sub-phenotypes
Chronic obstructive
pulmonary disease (COPD)
encompasses a number of
disease entities in the lung
that result in chronic airflow
obstruction. Classically,
COPD was subdivided into
two diseases: chronic
bronchitis and emphysema
(see the figure). Physicians
soon realized that most
patients with COPD suffered
from a combination of the
two components, with the
relative contribution of the two
varying from case to case. State-of-the-art
disease phenotyping of COPD subjects includes
an assessment of both components, and the integration
of pulmonary function tests (PFTs), computed tomography (CT) chest assessment for the presence of radiographic
emphysema, and history taking of symptoms and exposures, most notably for cigarette smoking. Detailed assessments
carried out in this way have demonstrated that some patients with emphysema have normal PFTs (technically these
patients do not have COPD) and that some patients with severe COPD do not have any evidence of emphysema. Of
course, patients most commonly exhibit a combination of the two disorders. Key components of this analysis include:
Forced vital capacity (FVC). The total volume of air that can be exhaled following a full inspiration. Results expressed in
litres and percentage predicted. A value of <80% predicted would be considered abnormal.
Forced expiratory volume in 1second (FEV
1
). The total volume of air that can be exhaled in 1second following a full
inspiration. Results expressed in litres and percentage predicted. A value of <80% predicted would be considered
abnormal. Disease severity in COPD is determined by this value, and is the basis for Global Initiative for Chronic
Obstructive Lung Disease (GOLD) classification, which is used in clinical studies.
FEV
1
/FVC ratio. The percentage of the total volume of air exhaled in the first second of exhalation. A value of <70%
indicates the presence of airflow obstruction and is the major criterion for a diagnosis of COPD.
Mouse models display the same level of disease heterogeneity as humans. The state-of-the-art mouse model to study
emphysema pathogenesis is cigarette smoke exposure. This model displays many of the key features of emphysema,
including permanent enlargement of the peripheral airspaces and a characteristic inflammatory cell infiltrate. However,
the model does not recapitulate the airways disease or bronchitis aspect of human COPD. This is mostly due to anatomical
differences between mice and humans, with mice having just five generations of branching airways compared with >20 in
humans. Additionally, mice do not display mucous hypersecretion in response to cigarette smoke. On the basis of recent
approaches, it is likely that novel genetic models will be able to induce mucous secretion in the mouse, which, when
coupled with cigarette smoke exposure, will more closely resemble human COPD. However, it is unlikely that such
manipulations will ever be able to reproduce the complexity of airways disease in human COPD.
REVI EWS
Genetics:
Process oxidant or noxious stress
EPHX, CYPs, MPO and NRF2
Cell cycle regulation:
Avoid apoptosis
Uncontrolled proliferation
Inammation:
Field propagation
Cytotoxic versus growth promoting
Cytokines:
NF-B activation
Regulate tumour microenvironment
Proteinases:
Matrix degradation
Release growth factors
?
COPD COPD with cancer
Tumour
Fields of injury. Lung epithelial and endothelial cell
apop tosis is a key feature of emphysema pathogene-
sis
50,51
, and is seemingly the polar opposite of the uncon-
trolled cellular proliferation that is observed in cancer.
However, viewed another way, the inability of some
lung cells to arrest or apoptose, owing to mutation or
epigenetic changes in the cell cycle regulatory machin-
ery (for example, TP53 or CDKN2A), might increase the
population of lung epithelial cells from which tumours
could arise. Debate persists as to whether apoptosis is a
primary event in response to cigarette smoke, or whether
it is secondary to cigarette smoke-induced inflammation
and matrix destruction
52
. Regardless, it is universally
accepted that lung epithelial cells are exposed to many
pro-apoptotic stimuli in COPD, and that lung cancers
arising in patients with COPD display a common cancer
hallmark: increased resistance to pro-apoptotic stimuli
53
.
Whether apoptosis in emphysema is induced by the
toxic and carcinogenic effects of cigarette smoke (a direct
or primary effect) or the indirect (secondary) effects that
are mediated by the hosts cytokine-rich inflammatory
response to smoke, or both, is important to consider
because injury to lung epithelial cells by the primary and
secondary effects of cigarette smoke is associated with
field cancerization, which is applicable to both COPD
and lung cancer
54
. The concept of a field of cells at risk
was first used to explain the presence of tissue that
appeared histologically normal adjacent to oral cancers
that shared some of the same molecular alterations as
the cancer itself
55
. With respect to the lung, there are
in essence two fields at risk airway epithelium and
peripheral airspace (alveolar) epithelium (FIG.2). A single
clone with a compromising genetic mutation (in TP53,
for example) could simply repopulate large portions of
the airway epithelium independently of inflammation,
and this has been described
56
. By contrast, synchronous
primary lung cancers in humans typically demonstrate
generally different mutation profiles, suggesting that the
cancers arose in the same field of injury, but from dif-
ferent cells of origin
57
. Most commonly, the combined
effects of cigarette smoke create large fields of injury
in which unique clones featuring commonly identified
genetic alterations (such as those in epidermal growth
factor receptor (EGFR), KRAS and TP53) are thought to
expand regionally
58,59
. Such expansion provides a larger
number of cells in which additional mutations could
occur, and increases the odds that a given cell could attain
the required number of mutations to become malignant.
Thus, airway epithelia in smokers share genetic similari-
ties and differences with neighbouring regions of injury
based on expanding clones in the samefield.
Developing neoplastic lesions also have the capacity
to expand and alter the field in which they originated.
Tumours developing in the LoxStopLox (LSL)-Kras
G12D

mouse model of lung cancer synthesize and release
numerous pro-inflammatory cytokines and chemokines,
including CXC motif chemokine ligand 1 (CXCL1),
CXCL2, CXCL5, TGF and CC motif chemokine ligand 2
(CCL2; also known as MCP1)
60
. This results in the recruit-
ment of myeloid cells to sites of tumorigenesis where
they promote lung tumour growth
61
. Additionally, these
macrophages and neutrophils represent an added source
of reactive oxygen species (ROS) that pose additional
genotoxic stress on cells residing in thefield.
Lung airway epithelial cells tend to follow a classical
pattern of tumour development that progresses from
metaplasia to dysplasia to carcinoma insitu and finally
to invasive carcinoma (SCCA), with each of these events
occurring in the field at risk. Genomic analysis of histo-
logically normal airway epithelial cells in smokers at
risk for lung cancer can distinguish between those who
have lung cancer and those who do not
62
. Furthermore,
signatures of PI3K hyperactivity can be found in both
dysplastic precursor lesions and in mature lung cancers,
highlighting a key early event
63
. However, this signature
does not confer risk ofCOPD.
Figure 1 | Candidate mechanisms linking COPD to lung cancer. There are several mechanisms associated with the
presence of chronic obstructive pulmonary disease (COPD) that might be associated with the development of lung
cancer. These include inflammation and associated cytokines, smoking, alterations to cell cycle regulation and the
presence of specific proteinases produced by immune cells and other stromal cells. Genetic and epigenetic changes
are also likely to confer a risk of developing one or both diseases. CYP, cytochrome P450; EPHX, epoxide hydrolase;
MPO, myeloperoxidase; NF-B, nuclear factor-B; NRF2, nuclear factor erythroid 2-related factor 2.
REVI EWS
Bronchoalveolar lavage
(BAL). To sample the contents
of the distal lung, physicians
insert a bronchoscope into the
smallest airway in which it can
fit. Once wedged into
position, saline is infused into
the lung, followed by suctioning
to return the fluid, which now
contains cells and proteins.
A similar paradigm has been suggested for the devel-
opment of lung ADCA. This model suggests that alveolar
epithelial cells progress to atypical alveolar hyperplasias
(AAHs), adenomas and finally to ADCA. This stepwise
progression is clearly visible in mice with activating muta-
tions in Kras
64
. In this case, the pathological features are
attributable to the cell of origin, known as the broncho-
alveolar stem cell (BASC)
65
. BASCs represent a potential
link between emphysema and cancer because they would
be under substantial pressure to replenish lung epithelial
cells that have apoptosed as a result of emphysema. Such
increased proliferation of stem cells is thought to increase
the risk of them acquiring pro-tumorigenic mutations.
Although the evidence for this hypothesis is strong in
mouse models, it remains unclear whether it is operative
in human lung ADCA in general. However, the identifica-
tion of mutations in EGFR, KRAS and TP53 in both AAH
and ADCA, supports the concept that these cancers progress
in a stepwise manner from a common cell of origin
66
.
Inflammation. Essentially all smokers develop mac-
rophage and neutrophil infiltration in their lungs, which is
itself not sufficient to cause COPD
67,68
. Patients with COPD
develop more pronounced inflammation when compared
with smokers without COPD, the extent of which posi-
tively correlates with disease severity
69
. It is noteworthy
that the destructive inflammatory cell infiltrates that are
operative in emphysema are found both in the airways
and in the airspaces, and therefore could contribute to the
development of both proximal and distal lung cancers.
Chronic inflammation is also a common feature
in lung cancer
70
. At first glance, the inflammatory cell
profiles seem to be similar in the two disorders, being
comprised of macrophages, neutrophils, and CD4
+
and
CD8
+
lymphocytes. Closer inspection, however, suggests
that the characteristics of the immune cells identified in
COPD differ from those found in lung cancer. Analysis
of bronchoalveolar lavage (BAL) fluid from COPD sub-
jects suggests that these cells are polarized towards a
Thelper1 (T
H
1) phenotype, as shown by cell surface
markers and substantial interferon- (IFN) production
71
.
This would suggest that alveolar macrophages in patients
with COPD would be skewed towards an M1phenotype,
which has not been clearly demonstrated. Lung macro-
phages are found in abundance in COPD, and display
a mixed phenotype of both M1 and M2 markers
72,73
.
However, all smoke-exposed lung macrophages damage
the lung matrix in that proteinase expression is fairly uni-
form, and seems to be independent of whether macro-
phages are of an M1 or an M2 phenotype. A simplified
view of the inflammatory infiltrate in COPD is that IFN
that is produced by T
H
1 cells elicits the production of
IFN-inducible cytokines from neighbouring CD8
+
lym-
phocytes
74
. These cytokines, which include CXCL10 (also
known as IP10), have been shown to induce the expres-
sion of macrophage elastase (also known as MMP12) from
macrophages through interaction with CXCR4. Release of
interleukin-8 (IL-8) from resident alveolar macrophages
and lung epithelial cells is jointly responsible for the pres-
ence of neutrophilic infiltrates in patients with COPD
75
.
Recent studies also point to an important role for T
H
17
lymphocytes in the propagation and the maintenance of
inflammation in COPD
76,77
.
Although a T
H
1 or cytotoxic profile would be desir-
able in the tumour microenvironment, it is rarely
encountered
78
. Most solid tumours have an immune cell
infiltrate polarized towards a T
H
2 phenotype and the
corresponding alternatively activated M2 macrophage
79
.
Copious monocytes and neutrophils at various stages of
development (often referred to as myeloid-derived sup-
pressor cells (MDSCs)) are frequently encountered in
lung cancer, and represent a commonality to COPD
8082
.
Whether from the activity of MDSCs, regulatory Tcells
(T
Regs
), co-regulatory molecules or other factors, the net
result is the suppression of cytotoxic T lymphocyte func-
tion and enhanced tumour viability
8385
. As has been done
for COPD, recent studies have explored the role of T
H
17
lympho cytes in solid cancers, although whether these cells
promote or suppress tumour development is unclear
86,87
.
The nature of inflammatory cells surrounding lung
cancers that reside in emphysematous lungs is the result
of competing disease microenvironments (FIG.3), and
must be considered in context. The cytotoxic environ-
ment identified in COPD would suppress existing cancers,
but it is conducive to tumour initiation. ROS supplied by
macrophages and neutrophils provide the necessary geno-
toxic stress for DNA adduct formation and subsequent
genetic mutation
88
. Once formed, early stage neoplasms
might alter the surrounding microenvironment by releas-
ing cytokines and chemokines (such as tumour necrosis
factor- (TNF), IL-1 and IL-6) that skew the immune
cell composition
89
. Nuclearfactor-B (NF-B) activation
in cancers and myeloid cells is a key step in this process
90

that results in the polarization of existing immune cell
populations to an alternative phenotype, as well as having
direct effects on the tumour cells.
Table 2 | Genetic susceptibilities to COPD and lung cancer
Gene COPD Lung cancer
SERPINA1 MZ heterozygotes associated with
COPD (P = 0.04)
151
A1AT carrier rate (12.3%) exceeded
expected control rate (P = 0.002)
152
MMP1 Combined MMP1 and MMP12 SNPs
associated with rapid decline in lung
function
115
MMP1 promoter SNP associated
with lung cancer risk (OR 1.8; 95%
CI 1.32.4)
153
CYP1A1 Homozygous *2A allele significantly
higher in severe COPD (P <0.01)
154
M1 homozygous genotype found
in 4.10% cancers versus 1.69%
controls
155
EPHX1 Increased COPD risk for exon 3
variant both as heterozygote (OR
3.0; 95% CI 1.27.1) and homozygote
(OR 2.4; 95% CI 1.15.1)
156,157
Lung cancer risk associated with
high EPHX activity (P <0.02)
158
CHRNA3
and
CHRNA5
CHRNA3 and CHRNA5 locus
significantly associated with both
radiographic emphysema (P <0.0002)
and airflow obstruction (P = 0.004)
38
CHRNA3 and CHRNA5 locus
strongly associated with lung
cancer in three independent
studies
40
MPO NA Reduced risk (OR 0.5; 95% CI,
0.290.88) of lung cancer with A/G
allele (reduced expression)
93
CHRNA3, cholinergic receptor, neuronal nicotinic, -polypeptide 3; CI, confidence interval; COPD,
chronic obstructive pulmonary disease; CYP1A1, cytochrome P450 subfamily 1, polypeptide 1;
EPHX1, epoxide hydrolase 1; MMP, matrix metalloproteinase; MPO, myeloperoxidase; MZ,
individuals that have one normal allele of SERPINA1 and a commonly encountered abnormal allele
designated Z; NA, not applicable; OR, odds ratio; SNP, single nucelotide polymorphism.
REVI EWS
Cancer
Mixed populations with
elds expanded by
inammation
Emphysema
with AAH
Clonal
expansion
Emphysema
Mixed
populations
Normal
alveoli
T cell
Macrophage
Neutrophil
Inhalation of
cigarette smoke
AAH
Oxidative and noxious stress. Tobacco cigarette smoke
delivers >4,000 distinct chemicals to the lungs with each
breath. Several of these substances possess harmful or
addictive properties, including nicotine, carbon mon-
oxide, 4-methylnitrosamino-1-[3-pyridyl]-1-butanone
(NNK), N-nitroso derivatives and polycyclic aromatic
hydrocarbons (PAHs). Xenobiotic metabolism is the
process by which host enzymes detoxify and eliminate
these noxious agents from the system
91
. The first step
is activation of the agent (by oxidation, reduction or
hydrolysis) by phaseI enzymes, which include haem
oxygenase 1 (HO1), myeloperoxidase (MPO), members
of the cytochrome P450 (CYP) family and microsomal
epoxide hydrolase (EPHX) family. This is followed by
conjugation by phaseII enzymes (most notably GSTs),
which allows excretion.
Although these systems exist to detoxify foreign sub-
stances, they can occasionally transform relatively harm-
less molecules into harmful carcinogens. For example,
PAHs (such as benzo-a-pyrene) are not themselves toxic.
Unfortunately, members of the CYP family and EPHX1
can generate metabolites of PAHs that are carcinogenic
92
.
As such, functional SNPs in some of these enzymes alter
the risk of COPD and/or lung cancer development, and
probably represent a component of genetic susceptibility
to both diseases (TABLE2).
MPO, found only in myeloid cells, is another phaseI
enzyme that is implicated in the inadvertent generation
of toxic metabolites. Accordingly, a lower functioning
SNP in MPO confers protection against lung cancer
93
.
An additional function of MPO is the generation of the
unique oxygen radical hypochlorous acid (HOCl
), which
additionally contributes to the oxidative stress provided
by cigarette smoke-induced inflammatory cell infiltrates.
The burden of ROS placed on lung epithelial cells
in the lungs of smokers is overwhelming. Direct effects
of cigarette smoke coupled with macrophage- and
neutrophil-derived ROS combines to place high genotoxic
and apoptotic stress on lung cells. The genes that encode
enzymes that can reduce this stress (such as catalase) con-
tain an antioxidant response element, which is activated by
the transcription factor, nuclear factor erythroid 2-related
factor 2 (NRF2)
94
. Nrf2
/
mice display increased epithelial
cell apoptosis and emphysema compared with wild-type
controls when exposed to cigarette smoke
95
. Therefore,
augmentation of NRF2 activity would seem to be an ideal
strategy to slow emphysema pathogenesis while reduc-
ing the genotoxic stress and the tumour-initiating burden
placed on lung epithelia in patients with COPD. There
are studies in Nrf2-deficient mice using primary and
metastatic tumours that support this strategy
96
. On the
basis of such results, drugs that enhance NRF2 activity
have been developed as novel chemopreventive agents
97,98
.
Unfortunately, the role of NRF2 in cancer has proved any-
thing but straightforward, with pro-tumour functions also
reported
99
, and recently reviewed in depth
100
. Most con-
cerning are the recent reports that activating mutations
in NRF2 confer resistance to conventional chemotherapy
and correlate with poor clinical outcomes, specifically
in NSCLC
101
. In this regard, NRF2 function is similar to
many of the key entities that potentially link COPD and
lung cancer. It has a different role in tumour initiation,
where its expression is associated with cancer prevention,
from the role it has in established cancer, where its expres-
sion can be growth promoting. Thus, future strategies to
manipulate NRF2 function in lung disease will require
application in a context-specificmanner.
The extracellular matrix and proteinases. Numerous
key pathogenic roles have been described for matrix-
degrading enzymes in both emphysema and lung can-
cer (TABLE3). Members of the cysteine proteinase, serine
proteinase and MMP families have been extensively
studied with respect to emphysema pathogenesis, espe-
cially those capable of degrading elastic fibres, an essen-
tial event in the development of this disease. Important
roles for non-elastolytic proteinases in emphysema
have also been described, most notably for MMP1 (also
known as collagenase I). Additionally, many of these
enzymes degrade the inhibitors of one another (A1AT
and the tissue inhibitors of metalloproteinases (TIMPs)),
Figure 2 | Fields at risk. A proposed model for lung adenocarcinoma development in
the setting of emphysema is shown on the left-hand side of the figure. Emphysema
develops in the setting of enhanced inflammation and excess proteinase burden. In this
context, a mutation develops (such as in TP53), which expands to form atypical alveolar
hyperplasia (AAH). The AAH eventually develops into an adenocarcinoma (shown by blue
cells) with assistance from a tumour-promoting inflammatory cell infiltrate. Proposed
models for airway epithelial cell-derived cancers are shown on the right-hand side of the
figure. Each different coloured cell in the lower airway depicts a unique mutation (purple,
green and red cells), all of which occurred in the same field. The middle airway depicts
the expansion of a single clone (shown in yellow), which has been described for TP53.
The upper airway depicts the most accepted model. In this case, there are single
mutation expansions (shown in green, purple and red) and areas where those fields have
developed additional mutations (dark purple and green). Each of these fields would be
expanded by the presence of surrounding inflammatory cell infiltrates.
REVI EWS
COPD:
Cytotoxic
Genotoxic
Matrix degrading
MMP12
ROS
NE
ROS
IL-4
IL-13
T
H
1
T
H
2
CD8
CD8
M1
T
H
17
T
H
17
M2
M2
M2
CCL2
IFN
CXCL10
VEGF
VEGF
Cancer:
Angiogenic
Myeloid suppressive
Growth promoting
IL-8
TGF
IL-1
IL-6
a b
thereby augmenting the others potency
102
. Some of these
proteinases may represent mechanistic links between
emphysema and lung cancer by contributing to lung tis-
sue destruction in emphysema and by promoting lung
tumour growth and invasiveness.
MMP9 (also known as gelatinase B) is produced from
numerous sources in the lung, most notably from alveo-
lar macrophages. Mmp9
/
mice are not protected from
cigarette smoke-induced emphysema
103
, which might be
because mouse MMP9 has reduced elastolytic activity com-
pared with the human enzyme. Indeed, MMP9 accounts
for a substantial proportion of the elastolytic capacity of
human alveolar macrophages
104,105
. Furthermore, MMP9
activity in BAL fluid correlates with the extent of emphy-
sema in human subjects
106
. Macrophage- and neutrophil-
derived MMP9 is essential for tumour angiogenesis in
several tumour types
107
. The extracellular matrix (ECM)
sequesters large amounts of vascular endothelial growth
factor (VEGF), which becomes biologically available on
MMP9 cleavage
108
. MMP9 has also been reported to gener-
ate angiostatic peptides from the ECM, although the pre-
dominant effect of the enzyme in mouse models has been
tumour promoting
109,110
.
MMP1 is an interstitial collagenase that contributes to
the growth of most solid tumours and promotes metas-
tasis formation. Mechanistically, MMP1 increases the
bioavailability of ligands for EGFR and degrades matrix
structures
111,112
, enabling tumour invasion. In a study of
metastatic lesions obtained from patients with breast
cancer, MMP1 was the most highly expressed gene in the
metastatic lesion
113
. With respect to emphysema, overex-
pression of MMP1 in transgenic mice creates the charac-
teristic airspace enlargement that is seen in emphysema
114
.
Furthermore, polymorphisms in the MMP1 promoter are
predictive of disease severity in patients with COPD
115
.
MMP12 is a fairly macrophage-specific proteinase
that is required for the development of cigarette smoke-
induced emphysema in mice
116
. It is one of the most
highly expressed genes in the alveolar macrophages of
subjects with COPD, and promoter polymorphisms gen-
erating increased MMP12 activity have been associated
with disease severity in COPD
117
. Although proteinase-
mediated destruction of lung matrix in emphysema is
a concerted effort between the different elastases, the
evidence for MMP12 as a pathological contributor
is strongest. Unfortunately, MMP12 is one of the rare
MMPs that is known to be tumour suppressive, essen-
tially rendering it a useless target for the treatment of
lung cancer
118,119
. MMP12 generates angiostatic peptides
from precursor proteins, most notably angiostatin from
plasminogen and endostatin from type XVIII collagen
120
.
NE probably represents part of the link between
COPD and lung cancer. Its role in emphysema patho-
genesis has been known for decades
121
, though it is
now recognized that NE simply contributes to elastic
fibre degradation, rather than being solely responsible
for it
122
. NE has recently been shown to promote lung
tumour growth in a Kras mouse model of lung adenocar-
cinoma
123
. NE enters tumour endosomes and degrades
a target substrate, insulin receptor substrate 1 (IRS1).
Depletion of cellular IRS1 affects PI3K signalling, which
is activated by a number of growth factors associated
with tumour progression. Whether NE predicts poor
outcomes in human lung cancer is not yet known.
However, NE activity has been correlated with disease
progression in invasive breast cancer
124,125
.
Proteinases can also affect disease pathogenesis in
an indirect manner by generating unique matrix frag-
ments that display novel biologically active properties
on cleavage. Such matrix fragments have been termed
matrikines. With respect to emphysema, matrix frag-
ments for elastin, laminin and collagen have all been
reported to possess chemotactic properties for inflam-
matory cells. More specifically, elastin fragments recruit
macrophages
126
, and both laminin 5 fragments
127
and
the collagen tripeptide repeat pro-gly-pro (PGP) recruit
neutrophils
128
. Inhibition of these peptide fragments sig-
nificantly alters inflammatory cell composition invivo,
suggesting that matrikines rival the more highly recog-
nized cytokines and chemokines for the maintenance
of chemotactic gradients in disease. Matrikines almost
certainly influence the inflammatory cell composition
surrounding tumours, although reports of direct effects
of these matrix fragments on cancer cells are lacking.
Populations at risk
Screening. The National Lung Screening Trial (NLST)
was a large, multicentre, clinical trial that compared
chest CT screening for lung cancer versus conventional
care (no screening). The results, published in 2011,
Figure 3 | Immune cell profiles in COPD and lung cancer. a | The immune cell
phenotype in chronic obstructive pulmonary disease (COPD) is T helper 1 (T
H
1)
predominant, as shown by cell surface markers and interferon- (IFN) production. CD8
+
T
lymphocytes release IFN-inducible cytokines that affect macrophage function, which are
of a mixed phenotype. Neutrophils release reactive oxygen species (ROS) and granular
contents enhancing tissue damage. b | Tumours secrete biologically active molecules at an
early stage, which polarize immune cells towards a T
H
2 phenotype, which is characterized
by interleukin-4 (IL-4) production. Macrophages are typically of the alternatively activated
M2 phenotype, which promote tumour growth and angiogenesis. Myeloid cells
(neutrophils and monocytes) of varying stages of development contribute to lung cancer
growth both directly (releasing growth-promoting substances) and indirectly by
suppressing cytotoxic T lymphocyte function. CXCL10, C-X-C motif chemokine 10;
MMP, matrix metalloproteinase; NE, neutrophil elastase; TGF, transforming growth
factor-; VEGF, vascular endothelial growth factor.
REVI EWS
Medicare
A national health insurance
programme in the United
States, and the largest payer of
health care services in the
United States.
-agonist
Inhaled drug that stimulates
the -adrenergic receptors
located on airway epithelial
cells. Their stimulation results
in the dilation of the airways.
Commonly used for the
treatment of asthma and
chronic obstructive pulmonary
disease.
showed a 20% reduction in lung cancer mortality for
the screening group
129
. Despite this, CT screening
for lung cancer has not become routine clinical prac-
tice, and Medicare in the United States has not revealed
whether they will pay for this screening. The three
major limitations to this approach are the number of
non-cancerous nodules that would require diagnostic
work-up, the very large population at risk (smokers)
and the costs for each. There is obvious interest in nar-
rowing this population at risk, knowing that only one
in nine smokers will develop lung cancer. Therein lies
the interest in COPD, which defines a population that
is at a particularly high risk for lung cancer. Ongoing
studies are attempting to improve the current scoring
systems for lung cancer risk
130
, by including factors such
as airflow obstruction and radiographic emphysema to
the already well-defined risk factors of age, smoking his-
tory and asbestos exposure. Additionally, COPD sub-
jects represent a population at a sufficiently high risk
for use in chemoprevention studies.
Chemoprevention and chemotherapy. Identification
of mechanisms linking COPD to lung cancer holds the
promise that these can serve as therapeutic targets for
COPD and chemopreventive measures for lung cancer.
There was enthusiasm over the report that the chronic use
of inhaled corticosteroids (ICS) in COPD reduced mortal-
ity from lung cancer
131
. However, large prospective trials
failed to demonstrate a survival benefit for the chronic use
of ICS with or without a long-acting -agonist
132
.
There are several ongoing clinical trials for lung
cancer chemoprevention that might also be relevant to
COPD. Interest in cyclooxygenase (COX) signalling as
a chemopreventive target is based on its success in other
malignancies, data from mouse models
133
and the asso-
ciation of increased COX2 expression with poor out-
comes in NSCLC
134
. COX2 generates prostaglandin E2
(PGE
2
) from the membrane phospholipid arachadonic
acid. PGE
2
promotes carcinogenesis in a variety of ways,
including resistance to apoptosis, increased angio genesis
and enhanced invasion
135
. A recent PhaseIIb clinical
trial using the COX2 inhibitor celecoxib in a high-risk
smoking population demonstrated a reduction in Ki-67
(proliferating antigen) labelling index in the bronchial
epithelium, which was used as a surrogate for reduced
cancer risk
136
. Unfortunately, celecoxib confers a risk of
cardiovascular disease, for which cigarette smokers are
already at an increased risk of developing
137
.
An alternative method to affect arachadonic acid
metabolism would be to enhance the production of pros-
tacyclin (PGI
2
), the counterpart to PGE
2
. Whereas PGE
2

is usually highly expressed in cancer, and less highly
expressed in normal lung tissue, the opposite is true
for PGI
2
(REF.138). As such, prostacyclin has tumour-
suppressive functions, and displays anti-proliferative and
anti-metastatic properties
139
. Oral prostacyclin (iloprost)
was recently studied in a randomized PhaseII study
using smokers with endobronchial dysplasia as the study
group. The iloprost group had a significant improvement
in endobronchial pathology
140
, which functioned as a
Table 3 | Candidate proteinases in emphysema and lung cancer
Proteinase Source Matrix substrates Promotes
emphysema?
Promotes
cancer?
Refs
Neutrophil
elastase
PMNs Elastin, CI, CIII, CIV, laminin,
fibronectin and TIMPs
Yes Yes 122,123
Proteinase 3 PMNs Elastin, CIV, laminin and
fibronectin
Yes ? 159
Cathepsin S Macrophages and
other cell types
Elastin, CI, CIII, laminin and
fibronectin
Yes Yes 160,161
Cathepsin L Macrophages and
other cell types
fibronectin
? Yes 162
Cathepsin K Macrophages and
other cell types
fibronectin
? ? 163
MMP1 Stromal cells CI, CIII and A1AT Yes Yes 112,114
MMP2 Stromal cells Elastin, CI, CIV, laminin,
fibronectin and A1AT
? Yes 164
MMP3 Stromal cells Elastin, CIII, CIV, laminin,
fibronectin and A1AT
No Yes 165
MMP8 PMNs CI, CIII and A1AT No No 166
MMP9 Macrophages, PMN
and other cell types
Elastin, CI, CIV, laminin and
A1AT
Yes Yes 106,107,
109
MMP12 Macrophages Elastin, CI, CIV, fibronectin,
laminin and A1AT
Yes No 116,119
MMP13 Stromal cells CI, CIII and CIV No Yes 167
MMP14 Stromal cells and
macrophages
CI, CIII, CIV, fibronectin and
laminin
? Yes 168,169
CI, collagen typeI; CIII, collagen typeIII; CIV, collagen typeIV; MMP, matrix metalloproteinase; PMNs, polymorphonuclear
leukocytes; TIMP, tissue inhibitors of metalloproteinase.
REVI EWS
surrogate end point for lung cancer risk. Additional tri-
als with iloprost will be required to demonstrate actual
decreases in lung cancer incidence.
Treatment options of proven benefit are limited for
patients with established COPD. For example, the only
drug that has been shown to prolong survival for COPD
subjects is supplemental oxygen, and this has been known
for decades
141
. Recent approaches have focused on path-
way hyperactivity, including direct and indirect inhibition
of NF-B. Theophylline indirectly suppresses NF-B by
activating histone deacetylase 2 (HDAC2), which restores
sensitivity to ICS in patients with COPD
142
. Direct target-
ing of NF-B has been shown to reduce airway inflamma-
tion and carcinogen-induced cancers in mice
143
. Clinical
investigations in humans are underway.
Patients with NSCLC have benefited from the recent
development of targeted therapies, most notably for
EGFR
144
and anaplastic lymphoma kinase (ALK)
145
.
Although EGFR and ALK mutations are only identi-
fied in small subsets of NSCLC, targeted therapies for
these pathways are of proven benefit. EGFR inhibition
has also been attempted in COPD subjects, as EGF and
its related ligands stimulate mucous hypersecretion
146
.
Unfortunately, the initial studies have been negative
in this respect. The completion of the recent genome-
sequencing studies for SCCA
147
and ADCA
148
has pro-
vided researchers with an improved description of the
mutations that occur in lung cancer. Once data emerge
identifying which of these represent driving mutations,
additional targeted therapies are likely tofollow.
Future directions
The identification of mechanisms linking COPD and
lung cancer has long been hampered by the heterogene-
ity of the disorders. The recently developed methods to
sub-phenotype COPD subjects has allowed researchers
to carry out enlightening clinical studies with respect to
which aspects of COPD pathogenesis confer lung cancer
risk. However, there are still several unanswered questions
regarding the links between COPD and lung cancer. For
example, does emphysema confer a local-regional risk
for lung cancer, or a global one? Which histological sub-
types of lung cancer are conferred by emphysema? And
which ones are influenced by airways disease? What is
the mutational profile of lung cancers arising on a back-
ground of COPD? There are few to no data regarding the
mutational status or pathway activation of tumours aris-
ing in such subjects, and whether they differ with coex-
isting COPD. Fortunately, studies using modern disease
sub-phenotyping to answer these questions are already
underway, along with a concerted effort to identify novel
biomarkers to narrow the population at risk. These studies
and answers to the above questions should help to guide
the direction of additional mechanistic studies.
A clear limitation of the field is simply that few studies
have examined human subjects or used preclinical models
in which both diseases are represented. Apart from the few
clinical studies assessing lung cancer incidence in COPD
subjects, essentially all of the studies reviewed here were
carried out in subjects with either COPD or lung cancer,
but not both. Additionally, the mechanistic possibilities
discussed here were mostly generated in mouse models
of cigarette smoke-induced emphysema or cancer, but not
both. Development of the necessary preclinical models
to simultaneously study both disorders will not be trivial.
As discussed in BOX1, mice are simply not a good model
to study the airways disease component of COPD, as a
result of the anatomical differences from human airways.
Scientists will have to use translational approaches and
expand current methodologies using bronchial epithelial
cell cultures and primary human lung cancer specimens.
Although mouse models of cigarette smoke-induced
emphysema and lung cancer can be combined, the results
will prove difficult to interpret. The dosages of cigarette
smoke required to generate emphysema in mice produce
a sufficiently cytotoxic inflammatory cell infiltrate, so
that discontinuation of smoking actually accelerates lung
tumour growth. Reported by Witschi and colleagues
149
in
1997, this observation has been conveniently ignored, but
must now be re-addressed if these models are to be used
for the combined study of these diseases. Adjustment of
cigarette smoke dosage and duration, as well as the care-
ful choice of cancer models, should enable investigators
to recapitulate the disease microenvironments that exist
in human subjects.
Although the increased cancer risk conferred by
COPD was the first lung disease to garner attention
in this way, it will not be the last. Idiopathic pulmo-
nary fibrosis (IPF) carries an approximately sevenfold
increased lung cancer risk
150
. A better understanding of
the mechanisms linking IPF and cancer should identify
new therapeutic targets, as is the hope for COPD. Finally,
there is one unequivocal preventive measure for COPD
and lung cancer: smoking abstinence. Although smoking
cessation will never lower COPD and lung cancer risk
to zero in asymptomatic smokers, it is the only clearcut
way to reduce their mortality, and should remain the top
clinical priority.
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FURTHER INFORMATION
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Competing interests statement
The author declares no competing financial interests.
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Despite well-documented health risks, a substantial

proportion of men and women in the developed world

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